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WO2007093587A1 - Utilisation de r-(-)-2,4-diamino-5-(2,3-dichlorophényl)-6-fluorométhylpyrimidine dans le traitement de troubles psychotiques - Google Patents

Utilisation de r-(-)-2,4-diamino-5-(2,3-dichlorophényl)-6-fluorométhylpyrimidine dans le traitement de troubles psychotiques Download PDF

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Publication number
WO2007093587A1
WO2007093587A1 PCT/EP2007/051380 EP2007051380W WO2007093587A1 WO 2007093587 A1 WO2007093587 A1 WO 2007093587A1 EP 2007051380 W EP2007051380 W EP 2007051380W WO 2007093587 A1 WO2007093587 A1 WO 2007093587A1
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pyrimidine
pharmaceutically acceptable
prodrug
diamino
solvate
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Charles Large
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Glaxo Group Ltd
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Glaxo Group Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • This invention concerns the use of the compound R(-)-2,4-dlamino-5-(2,3-dichiorophenyi)- 6-fluoromethyl pyrirnidi ⁇ e, or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of psychotic disorders, for example schizofrenia.
  • R(-)-2,4-diamino-5- ⁇ 2,3-dicftlorophenyl)-64luoromethyl pyrirnidine having formula (I) below, and some salts thereof, its preparation and us use in the treatment of pain, functional bowel disorders, epilepsy, bipolar disorders and unipolar depression, dependence, and neurodegenerative diseases are disclosed in published International Patent application WO 97/09317 and in the corresponding patents EP0879230B and US 6,124,308.
  • the present invention ⁇ $ concerned with the use of R(-)-2.4-diamin ⁇ -5-(2.3- dicbloro ⁇ heny ; )-6-ftuorornethy! pyrimidine of formula (!), or pharmaceutically acceptable salts, solvates or prodrugs thereof, either as monotherapy or in combination with another therapeutic agent, for the treatment of the above mentioned psychotic disorders.
  • the present invention provides the use of R(-)-2,4-diamino-5-(2,3- dichlorophenyi)-6-fiuorornethyl pyrimidine of formuia (I) 1 or pharmaceutically acceptable salts, solvates or prodrugs thereof, in the treatment of psychotic disorders.
  • the invention provides the use of R ⁇ -)-2,4-dtamiPo-5-(2,3- dich!orophenyl)- €-ftuoromethy! pyrimidine of formula (I) 1 or pharmaceutically acceptable salts, solvates or prodrugs thereof, in the manufacture of a medicament for the treatment of psychotic disorders.
  • the invention provides a method of treatment of psycnot ⁇ c disorders comprising administering Io a human a therapeutically effective amount of R ⁇ -)-2,4- diam!no-5-(2,3-dichiorophenyl)-6-fi ⁇ orornethyl pyrimidine of formula (!). or pharmaceutically acceptable salts, solvates or prodrugs thereof.
  • the terms describing the indications used herein are classified in the Diagnostic and Statistical Manual of Mentai Disorders, A ⁇ h Edition, published by the American Psychiatric Association (DSM-IV) and/or the international Classification of Diseases, 10th Edition (ICD-10).
  • DSM-IV Diagnostic and Statistical Manual of Mentai Disorders
  • ICD-10 international Classification of Diseases, 10th Edition
  • Numbers irs brackets after the listed diseases below refer to the classffication code in DSM-IV.
  • Psychotic disorders of the invention include: Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), undifferentiated Type (295.90) and Residua* Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type: Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-induced Psychotic Disorder Including the subtypes With Delusions (293.81 ⁇ and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).
  • schizophrenia also includes cognitive impairment associated with schizophrenia and dementia in schizophrenia.
  • the psychotic disorder is Schizophrenia, including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295,90) and Residual Type (295.80).
  • R(-)-2 > 4-diamino-5-(2,3-dichforophenyi ⁇ - ⁇ -fiuoromethyi pyrir ⁇ idine and salts and solvates thereof are described in PCT publication No. WO 97/09317, published 13 March 1997, and corresponding US 6,124,3O8A and EP087923081.
  • R(-)-2,4-diamino-5-(2,3- dich!oro ⁇ henyi)-6-fiuorornethy! pyrimidine may be prepared by any method described in WO 97/09317. and equivalent patent applications. The disclosure of this reference is incorporated herein in Its entirety.
  • R ⁇ -)-2,4-diamino-5-(2,3-dicrrtorophenyl)-6-f!uoromethyl pyrimidine may be isolated following work-up in the form of the free base.
  • Pharmaceutically acceptable acid addition saits of R(-)-2.4-diamino-5-(2,3-dichiorophenyl)-6-fluoromethy! pyrimidine may be prepared using conventional means,
  • references herein to R ⁇ -)-2,4-diammo-5- ⁇ 2,3-dichloropheny!-6- fluorornethy! pyrimidine be interpreted to mean that the pharmaceutically acceptable saits, solvates ar>d prodrugs of R ⁇ -)-2.4-diami ⁇ o-5-(2,3-dich!orophenyi)-6-fiuoromethy! pyrimidine may also be employed.
  • a pharmaceutically acceptable salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • Suitable addition salts are formed from acids which form non-toxic salts and examples are hydrochloride, hydrobroroide, hydro! odide, sulphate, disuiphate, nitrate, phosphate, hydrogen phosphate, acetate, maieafe, malate, fumarale, lactate, tartrate, citrate, formate, gluconate, succinate, psruvate, oxalate, oxaloacetate, trifiuoroaceiate.
  • saccharate be ⁇ zoate, methansulphcnate, ethanesuiphonale, benzenesulphonate, p- toiuensulphonate, rnethanesuiphomc, ethanesuiphorsiC, p-toluenesulphonic, and isethionafe.
  • prodrug means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects.
  • Pharmaceutically acceptable pro ⁇ rugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Deliver/ Systems, Vol. 14 of the A. C. S. Symposium Series, Edward 3. Roche, ed., BioreversiDie Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987. and in D. Fleisher, S. Ramon and H. Barbra ' 'improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 13(2) 115-130, each of which are incorporated herein by reference.
  • Prodrugs are any covalently bonded carriers thai release R(-)-2,4-diam ⁇ no-5-f'2 s 3- dichloropheny!)-6-fiuoromethyl pynmsdine in vivo when such prodrug is administered to a patient.
  • Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine rnampuiation or in vivo, yielding the parent compound.
  • Prodrugs include, for example, R(-)-2.4-dtam;no-5- ⁇ 2,3-d ⁇ chioropheny!- 8-tluoromethyl pyrimidine wherein amine groups are bonded to any group that, when administered to a patient, cleaves Io form the amine group.
  • representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of amine functional groups of R(-)-2,4-diaminc ⁇ 5-(2,3-dich!orophenyl)-6- fiuoromethyi pyrimidine.
  • compositions are co ⁇ venientiy administered in the form of pharmaceutical compositions.
  • Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable earners or e*
  • R(-)-2,4-diamino-5-(2,3-dichloropheny!)-6-fluoromefhyl py ⁇ midine, or pharmaceutically acceptable salts, solvates or prodrug thereof may be formulated for administration in any suitable manner. They may, for example, be formulated for topical administration or administration by inhalation or. for example, for oral, transdermal or parenteral administration.
  • the pharmaceutical composition may be in a form such that it can effect controlled release of R(-)-2,4-dtaffiino-5-(2,3-dichlorophenyi ⁇ -6-fluoromethyl pyrimidine, or pharmaceutically acceptable salts, solvates or prodrug thereof.
  • compositions may contain from 0.1% by weight, for example from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will for example contain from 0.5-1000 mg of the active ingredient.
  • the dosage as employed for aduit human treatment may range from 0.5 to 3000 mg per day depending on the route and frequency of administration. For oral administration a typical dose may be in the range of 0.5 to 1500 mg per day. for example 0.5 to 1000 mg per day.
  • the dosages of the drugs used in She present invention may, in the final analysis, be set by the physician in charge of the case, using knowledge of the drugs, the properties of the drugs in combination as determined in clinical trials, and the characteristics of the patient, including diseases other than that for which the physician is treating i ⁇ )e patient.
  • the pharmaceutical composition may take the form of, for example, tablets (including s ⁇ b- ⁇ nguai tablets), capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.
  • the pharmaceutical composition may be given in the form of a transdermal patch, such as a transdermal iontophoretic patch.
  • the pharmaceutical composition may be given as an injection or a continuous infusion (e.g. intravenously, intravascular ⁇ or subcutaneousiy).
  • compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain forrnuiatory agents such as suspending, stabilising and/or dispersing agents.
  • forrnuiatory agents such as suspending, stabilising and/or dispersing agents.
  • these may take the form of a unit dose presentation or as a muitidose presentation preferably with an added preservative.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle.
  • R(-)-2,4-diam ⁇ no-5-(2.3-dichiorcphenyl)-6-fiucromethyl pyrirnidine, or pharmaceutically acceptable salts, solvates or prodrug thereof, may also be formulated as a depot preparation.
  • Such long acting formulations may be administered by implantation (for example subcutaneousiy or intramuscularly) or by intramuscular injection.
  • R(-)-2,4 ⁇ diam!no ⁇ 5-(2,3-dich!orophenyi)-6-Huoromethyi pyrimidine, or pharmaceutically acceptable salts, solvates or prodrug thereof may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soiubie derivatives, for example, as a sparingly soluble salt.
  • a proposed daily dosage of R(-)-2,4-diamin ⁇ -5- ⁇ 2,3-dich!oropher ⁇ yi)-8-fluorornethyl pyrimidine for the treatment of man is O.OImg/kg to 500mg/kg, such as Q.05mg/kg to 100mg/kg, e.g. 0.8-3.0mg/kg, which may be conveniently administered in 1 to 4 doses.
  • the precise dose employed wili depend on the age and condition of the patient and on the route of administration. Thus, for example, a daily dose of 0.25mg/kg to 10mg/kg may be suitable for systemic administration.
  • R(-)-2,4-diam ⁇ no-5-(2,3- dichiorophenyl)-6-f!uoromethyi pynmidi ⁇ e, or pharmaceutically acceptable salts, solvates or prodrug thereof, are ⁇ sed in the form of tablets for oral administration.
  • the invention concerns the use of R ⁇ -)-2,4-diam!n ⁇ -5-(2.3-dichiorophenyl)-6- fluoromethyi pyrimidine, or pharmaceutically acceptable salts, solvates or prodrug thereof, as monotherapy or in combination with another therapeutic agent for the treatment of psychotic disorders as above defined.
  • R(-)-2,4-diamino-5-(2,3-dichioropheny! ⁇ -6-f1uoromethyl pyrimidine, or pharmaceutically acceptable salts, solvates or prodrug thereof, may be used in combination with the following agents to treat or prevent psychotic disorders: i) neuroleptic drugs; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden.
  • procyciidine and trihexyphenidyl include antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iit) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example choir ⁇ esterase inhibitors (such as tacrine, donepezii, rivastigmme and galantami ⁇ e).
  • Neuroleptic drugs include both classical and atypical neuroleptics.
  • neuroleptic drugs are also intended to include antipsychotic agents.
  • Antidepressant drugs include serotonin reuptake inhibitors (such as citaiopram. escitaiopram, fluoxetine, paroxetine and sertraline); dual serotonin/noradrenaiine reuptake inhibitors (such as venlafaxine, duioxetine sn ⁇ mil ⁇ a ⁇ pran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, irniprarnine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide. phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).
  • serotonin reuptake inhibitors such as
  • Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divaiproex, carbamazepine, lamotrigi ⁇ e, gabapenttn, topiramate and iiagabine.
  • Anxiolytics include benzodiazepines such as alprazolam and lorazeparn,
  • R ⁇ -)-2 4-diamino-5- ⁇ 2.3-cichiorophe ⁇ y!-6-fluoromethyi pyrimidine, or pharmaceutically acceptable salts, solvates or prodrug thereof, may also be used in combination with other therapeutic agents.
  • the invention thus provides, -n a further aspect, a combination comprising R(-)-2,4- diamino-5-(2,3-dichlorophenyl)-6-fiuoromethyl pyrimidine, or a pharmaceutically accectable salt, solvate or prodrug thereof, together with a further therapeutic a ⁇ ent.
  • the invention thus provides, in a further aspect, a combination comprising R(-)-2,4- diamino-5-(2,3-diChiorophenyi)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with a neuroleptic drug.
  • the invention thus provides, m another embodiment, a combination comprising R(-)-2.4- diamino-5-(2,3-dichloropheny1)-6-fluoromethy! pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with 3- ⁇ 2-[4-(6-fluoro- 1 ,2- ben2isoxazol-3-y!-1 - ⁇ iperidinyl]ethyi ⁇ -2 ⁇ methyl-6,7,8,9-tetrahydro-4H-py ⁇ do(1 ,2- a ⁇ pyrimidin-4-one. or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the invention thus provides, in one embodiment, a combination comprising R(-)-2,4- diamtno-5- ⁇ 2,3-dichlorophenyi)-6-fiuoromethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with 3-hydroxy-2-phe ⁇ yi-/V-f(1 S)-I- pheny!propy!]-4-quinoiinecarboxamide, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the invention thus provides, in a further embodiment, a combination comprising R(-)-2,4- diamino-5-(2 ) 3-dichiorophe ⁇ yi)-6-f! ⁇ oronnethyl pyrimidine. or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with 7-[4-(4-chloro-benzy!oxy)- benzenesuifonyl]-8-metho ⁇ y-3-methyi-2,3,4.5-tetrahydr ⁇ -1 W-3-benzazepine. or a pharmace'jticaliy acceptable sal, solvate or prodrug thereof.
  • the invention thus provides, in a further aspect, a combination comprising R(-)-2,4- diamino-5-(2,3-dichi ⁇ rophenyi)-6-fruorornethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with a further therapeutic agent for use in therapy,
  • the invention thus provides, in one embodiment, a combination comprising R(-)-2,4- diamino-5-(2,3-dich!orophenyi)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with a neuroleptic drug for use in therapy.
  • the invention thus provides, in one embodiment, a combination comprising R(-;-2,4- diamino-5-(2,3-dichl ⁇ rGphenyi)-6-f!uoromethyl pyrimidine. or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with 3- ⁇ 2-[4- ⁇ 6-fIuoro-1 ,2- benzisoxazol-3-yl)-1-piperidi ⁇ yi ⁇ ethyi ⁇ -2-methyl-6,7.8,9-tefrahydro-4W-pyrido[1 ,2- a]pyrim!din-4-one. or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in
  • the invention thus provides, in one embodiment, a combination comprising R(- ⁇ -2,4- diam ⁇ no-5-(2,3-dichlorophanyi)-6-f!uoromefhyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with 3-hydroxy-2-pheny ⁇ - ⁇ /-[(1 S)-1- ⁇ henyipropyO-4-quinoiineoarboxarnide, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in therapy.
  • the invention thus provides, in another embodiment, 3 combination comprising R ⁇ - ⁇ -2,4- dtamino-5-(2,3-dichiorophenyl)-6-fiuoromethyl pyrimidine, or a pharmaceuiicaliy acceptable salt, solvate or prodrug thereof, together with 7-[4-(4-chlor ⁇ -benzyloxy)- benzenesulfonyi]-8-methoxy-3-meihyi-2,3,4,5-te!rahydro-1H-3-benzazep!ne, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in therapy.
  • the present invention provides the use of a combination comprising R ⁇ - )-2,4-diarnino-5-(2,3-dichloropheny!-6-fluoromethy! pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a neuroleptic drug for ⁇ ne treatment of psychotic disorders as above defined.
  • the present invention provides the use of a combination comprising R(- ⁇ -2.4-diamino-5-(2,3-dichiorophenyl)-6-fiuorornethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and 3- ⁇ 2-[4-(6-fiuoro-1 ,2- oenzisoxazo[-3-yl)-1 -piperidinyi]efhyl ⁇ -2-rr!eihyi-6.? > 8,9-tetrahydro-4H-pyrido[1 ,2- ajpyrimidin-4-one, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the treatment of psychotic disorders as above defined.
  • the present invention provides the use of a comoination comprising R(-)-2,4-diamino-5-(2,3-dichlorophenyi)-6-f!uoromethyl py ⁇ midine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and 3-hydroxy-2-pheny!- ⁇ /- [(1 S)-1-phenylpropy!]-4-quino ⁇ necarboxamide, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the treatment of psychotic disorders as above defined.
  • the present invention provides the use of a combination comprising R ⁇ -)-2,4-diamino-5-(2,3-dscnSorophenyl)-6-fluoromethyi pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug (hereof, and 7-[4-(4-chloro- benzyloxy)-benzenesuifonyi]-8-me ⁇ hoxy-3-methyl-2,3,4,5-tetrahydro-i H-3-benzazepine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the treatment of psychotic disorders as above defined.
  • the present invention provides the use of a combination comprising R ⁇ - )-2,4-diamino-5-(2,3-cliChlorophenyi ⁇ -6-ffuorofnethyl pyrimtdine. or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a neuroleptic drug in the manufacture of a medicament for the treatment of psychotic disorders as above defined.
  • the present invention provides the use of a combination comprising R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and 3- ⁇ 2-[4-(6-fiuoro-1.2- ben2isoxazol-3-yl)-1-pipendinyl ⁇ ethyi ⁇ -2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1 ,2- ajpyrimidin-4-one. or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for the treatment of psychotic disorders as above defined.
  • the present invention provides the use of a combination comprising R(-)-2,4-diamino-5-(2.3-dichiorophenyl)-6-fiuoromethy! pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and 3-hydroxy-2-phenyl- ⁇ /- [(1 S)-1 -pheny!propy! ⁇ -4-quino!inecarboxamide, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in She manufacture of a medicament for the treatment of psychotic disorders as asove defined.
  • the present invention provides the use of a combination comprising R(-)-2 t 4-diamino-5- ⁇ 2,3-dichiorophenyi)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and 7-[4-(4-chloro- benzy!oxy)-benzenesulfonyl]-8-methox7-3-methyi-2,3,4,5-teirahydro-1 H-3-ber!za2epine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for the treatment of psychotic disorders as above defined.
  • the present invention provides a method of treatment of psychotic disorders comprising administering to a human a therapeutically effective amount of a combination comprising R(-)-2,4-diamino-5-(2.3-dichiorophenyl)-6-fluoromethyl pyrimidine of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a neuroleptic drug.
  • the present invention provides a method of treatment of psychotic.
  • the present invention provides a method of treatment of psychotic disorders comprising administering to a human a therapeutically effective amount of a combination comprising R(-)-2,4-diamino-5-(2.3-dichlorophenyf)- ⁇ -fluoromethyl pyrimidine of formula (I) 1 a or pharmaceutically acceptable salt, solvate or prodrug thereof, and 3- hydroxy-2-phenyl- ⁇ /-[ ⁇ 1 S)- 1 -phenyipropylH-quinolinecarboxarnide, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the present invention provides a method of treatment of psychotic disorders comprising administering to a human a therapeutically effective amount of a combination comprising R ⁇ -)-2,4-di3mino-5-(2,3-dichlorophenyi)-6- fl ⁇ oromethyl pyrimidine of formula (I), or a pharmaceutically acceotabie salt, solvate or prodrug thereof, and 7-f4-(4-chloro-benzyioxy)-be ⁇ zenesuifonyl)-8-methoxy-3-rnethyl- 2,3,4.5-tetrahydr ⁇ -1 ⁇ H-3-benza2eptne I or a pharmaceutically acceptable sail, solvate or prodrug thereof.
  • a combination comprising R ⁇ -)-2,4-di3mino-5-(2,3-dichlorophenyi)-6- fl ⁇ oromethyl pyrimidine of formula (I), or a pharmaceutically acceotabie salt, solvate or prod
  • compositions composing a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise 8 further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously, in separate or combined pharmaceutical compositions.
  • the present invention provides the use of R ⁇ -)-2,4-d ⁇ arnino-5-(2,3- dichlorophenyi)-6-fluoromethy! py ⁇ midine, or a pharmaceutically acceptable sail, solvate or prodrug thereof, in combination with a neuroleptic drug for the manufacture of a medicament for the treatment of psychotic disorders as defined above.
  • the present invention provides the use of R(-)-2,4-diarnino-5-(2,3- dichiorophe ⁇ yl ⁇ -6-fiucromethyt pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination with a neuroleptic drug for the treatment of psychotic disorders as defined above.
  • the present invention provides a method of treatment of psychotic disorders comprising administering to a human a therapeutically effective amount of R(-)- 2 1 4-diamino ⁇ 5-(2,3 ⁇ dichiorophenyi)-6-fiuofomethy! pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination vv-th a neuroleptic drug for the treatment of psychotic disorders as above defined.
  • R ⁇ -)-2,4-diamino-5- ⁇ 2,3-d ⁇ chlorophenyl)-6- fl ⁇ orornethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, either as monotherapy or in combination with a neuroleptic drug is useful for the treatment of schizophrenia.
  • neuroleptic drugs examples include, but are not limited to; butyrophenon ⁇ s, such as haioperidof, pimozide, and droperi ⁇ oi; phenothiazines. such as chiorpromazine, thioridazine, m ⁇ soridazine.
  • thi ⁇ xanthenes such as thiothixene and chlorprothixene
  • thienobenzodiazepines dibe ⁇ zodiazepi ⁇ es
  • benzisoxazoles dibenzothiazepines
  • irnidazolidinones benziso- thiazoiyl-piperazines
  • tiiazine such as iamotrigine
  • dibenzoxazepines such as ioxapine
  • dihydroindolones such as molindone
  • aripiprazoie and derivatives thereof that have antipsychotic activity.
  • neuroleptic drugs examples include neuroleptic drugs that may be selected for use in the present invention.
  • Examples of tradenames and suppliers of selected neurolept c drugs are as follows clozapine ('available jnde- tne rradename CLOZARIL®, rrcm Myian, Zenith Goidime UDL Novartis) olanzapine ⁇ avaiiabie under the tradename ZYPREX ⁇ , from Lilly ziprasidone (available under the tiadename GEODON®, from Pfizer) risperidone (available under the tradename R[SPERC 5 ALS Iron Ja ⁇ ssen), qcet.aome fumarate (available under !he traderame SEROOUEL®, fro ⁇ AstraZeneca), halope ⁇ do!
  • fluphenazme available under the tradename PROLIXlN E-, from AIN, Copley, Sche ⁇ no, leva, and American Pharmaceutical Partners, Pasadena
  • thiothixene available under the tradename NAVANE®, from Pfizer
  • tri f luoperazine (10-l3-(4-m* s ⁇ hyi-1-p ⁇ peraz ⁇ nyi ⁇ prooyll-2- (t ⁇ fl ⁇ oromethyl)phenothiazne dihydrochlo ⁇ de, available under the tradename STELAZINE?;, from Sn thKf ⁇ eBeecham, cerphenaz ⁇ e (available under the tradename TRLAFON'S Iron Sche ⁇ ng), thioridazine (available under ihe tradename MELLARIL®, trom Novartis Roxane, HiTech, Teva, aid Aipharma) .
  • mo irdone (avai ab ⁇ e under the tradenane MOBAN® from Endo). and ioxapine (available under ihe tradename LOXi ⁇ ANE®; from Watson).
  • benperidol Gibimon®
  • perazine Taxilan®
  • melperone Engelperone
  • neuroleptic drugs include promazine (available under the tradename SPARINE®), triflurpromazine (available under the tradename VESPRIN®). chiorprothixene (available under the tradename TARACTAN®), droperidoi (available under (he tradename INAPSINE®), acetophenazine (available under (he tradename TINDAl®;), prochlorperazine (available under the tradename COMPAZINE ⁇ ). rnethotrimeprazin ⁇ (available under the tradename NOZI NAN®), pipotiazine (available under the tradename PiPOTRtL®). ziprasidone, and hoperidone.
  • promazine available under the tradename SPARINE®
  • triflurpromazine available under the tradename VESPRIN®
  • chiorprothixene available under the tradename TARACTAN®
  • droperidoi available under (he tradename INAPSINE®)
  • acetophenazine available under (he tradename TINDAl®;
  • neuroleptic drugs include the compounds disclosed in the patent application WO03/099786, filed by the same Applicant o'> the present invention.
  • -8-rnethoxy-3-methyl-2 1 3,4,5- te(rahydro-1 /-/-3-be ⁇ zazepine and Its pharmaceutically acceptable salts are examples for use in the present invention.
  • the neuroleptic drug within the preseni invention is 7-(4-(4-chiof ⁇ - benzyfcxy)-benzenesuifonyi]-8-rf>ethoxy-3-methyl-2,3,4,S-tetrahydro-1H-3-benzazepine male ⁇ le; its manufacture is described in PCT Publication Number WO2005/051916. The disclosure of this reference is incorporated herein in its entirety.
  • the neuroleptic drug is 3-hydroxy-2-pheny!- ⁇ /-[(1 S)-1- phenyipropyl]-4-quinoiinecarboxannide, or pharmaceutically acceptable salts, solvates or prodrugs thereof; its manufacture and pharmacological activity is described in PCT Publication Number WO9S/32948. The disclosure of this reference is incorporated herein in its entirety.
  • neuroleptic drugs include risperidone and aripiprazole (from Bristoi Myers Squibb Company, see e. g. Stahl SM; Dopamine-system stabilizers, aripiprazole and the r ⁇ e"xi generation of antipsychotics, part i ,”goldi!ocks"- aclions at dopamine receptors; J, Clin. Psychiatry 2001 ,62,1 1 : 841 -842).
  • the neuroleptic drug within the present invention is 3- ⁇ 2-[4-(6-fiuoro-1 !
  • Risperdal® 2-benzisoxazoi-3-yi)-1-pipe ⁇ dinyl)ethyl ⁇ -2-me(hy!-6, 7,8,9- tetrahydro-4H-pyr!do[i ,2-ajpyrimidin-4-one (risperidone or Risperdal®), its manufacture and pharmacological activity is described in EP 0 196 132.
  • Risperidone acts as an antagonist to neurotransmitters, in particular dopamine, and is used for the treatment of psychoses.
  • the neuroieptic risperidone can be administered at a dose of 2-6 mg/day, preferably 4-5 mg.
  • the dose for R(- ⁇ -2,4-diamino-5 ⁇ (2,3-dichiorophenyi)-6- fluoromethyl pyrimidine may range from 0,25 mg/kg to 5 mg/kg, preferably 0.8 mg/kg to 3.0 mg/kg.
  • ine administration occurs once daily.
  • the invention is also directed to a novel kit-of-parts that is suitable for use in the treatment of psychotic disorders as above defined comprising a first dosage form comprising a neuroleptic drug and a second dosage form comprising R(-)-2 i 4-diamino-5- ⁇ 2.3- dichloropheny!-6-(!uoromethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for simultaneous, separate or sequential administration.
  • the dosage form comprising a neuroieptic drug and the second dosage form comprising R(-)-2,4-diamino-5-(2,3-dichlorophenyi)- ⁇ -fl ⁇ oromethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, are administered simultaneously.
  • the dosage form comprising a neuroleptic drug and the second dosage form comprising R ⁇ - ⁇ -2,4-diamino-5-(2.3-dichioropheny!-6-fluoromethyl pyrimidine. or a pharmaceutically acceptable salt, solvate or prodrug thereof, are administered separately.
  • the dosage forms of pharmaceutical kit-of-parts may be administered enteraily (orally) or parenteraliy.
  • Parenteral administration includes subcutaneous, intramuscular, intradermal, intramammary, intravenous, and other administrative methods known in the art.
  • Enteral administration includes solution, tablets, sustained release capsules, enteric coated capsules, and syrups.
  • kits comprising R ⁇ -)-2,4-ciiamino-5-(2,3-dichiorophenyl)-6- ⁇ uoromethyl py ⁇ mitisne , or pharmaceutically acceptable saits, solvates or prodrug ihereof, ,and a neuroleptic occurs enteraily (orally), in form of tablets.
  • tranquilizers may be used for the treatment of agitation, anxiety or sleep disturbances
  • iorazepam is used, which belongs to the class of benzodiazepines.
  • references herein to "treatment” extend to prophylaxis, prevention of recurrence and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions
  • Recrystailised material (0.5227g) from step 2 was dissolved under warming in absolute etnano,' (25ml). The resuming solution was left to coo! overnight. The rnoiher liquor was then decanted. The remaining white crystalline solid was washed with ethanoi (1 ml) and dried at 50 " C in a vacuum oven overnight; yield (0.397g) 76%. The ratio of R(-) ena ⁇ tiomer to S(+)enantiomer was 99.8:0.2.
  • the crystalline salt from step 3 was then basified with 2M NaOH solution. Thus, distilled water was added to the salt. The resulting siurry was stirred at room temperature. Then 2 M NaOH was added until pH 12 was maintained. The resulting suspension was left for 1 hour. Then the solid was filtered off and washed with water. The wet solid was dried at 50 ° C in vacuo to give a white solid.
  • the white crystalline soiid obtained was dried at 5Q " C in vacuo for 6 hours,
  • the ratio of R(-)enantiomer io S(+)enanliomer in the dried crystalline material obtained (22g) was >99:1 .
  • the study may be performed as a muitice ⁇ ter, double-blind, placebo controlled randomised, parallel group determinatior. of efficacy of compound R(-)-2,4-diamino-5-(2,3- dichlorophenyi)-6-fluorornethyl pyrimidine in combination with an atypical antipsychotic agent approved for the treatment of schizophrenia vs an atypical antipsychotic agent approved for the treatment of schizophrenia with placebo.
  • the study may be performed using a therapeutic dose within the prescribed guidelines of Risperidone.
  • the patients may receive an appropriate dose of the atypical antipsychotic agent ⁇ defined antipsychotic agent or antipsychotic) ,and, depending on which group they belonged, a therapeutically effective amount R(- ⁇ -2,4-dian-iino-5-(2,3-dich!orophenyl)-6-fluoromethyl pyrimidine once daily or placebo over 12 weeks after a brief wash-out period of earlier antipsychotic medication.
  • a benzodiazepine preparation (mostly iorazepam) may be prescribed, if necessary.
  • Patients with agitation, anxiety, or sleeping problems may be also medicated with Iorazepam during the study.
  • biperide ⁇ may be monitored as a possible indicator for side effects of the antipsychotic medication.
  • the plasma levels of this drug may be monitored during the study.
  • the statistics may be performed according to the criterion of "last observation carried forwarcs" (LOCF), i. e., the last PANSS scores of the patients who dropped out before the end of the study were carried forward io all subsequent observation days.
  • LOCF last observation carried forwarcs
  • t-tests for independent samples may be employed VVHh reference to the underlying hypothesis of a better outcome of R(-)-2,4-diamino-5- (2,3-dichioropheny!-6-fluoromethyl pyhmidirse/aniipsychotic agent group, a significance of p ⁇ 0.05 may be calculated in the one-tailed i-test and used as the basis for the estimation of the sample size (statistical power) and for the comparison of the groups. For ail other comparisons, two-tailed t-tests may be used,
  • R(-)-2,4-diamino-5-(2.3-dtchlorophenyl)-6-fi ⁇ oromethyl pyrimidine and a atypical antipsychotic agent according to the present invention thus may show improved results compered to the mo ⁇ opreparation of the atypical antipsychotic agent with regard to effectiveness in the treatment of schizophrenia.
  • R(> ⁇ -2,4-diarnino-5-(2,3-dichlorophenyl)- ⁇ -fluoromethyi pyrimidine or a pharmaceutically acceptable derivative thereof, ⁇ 1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
  • Example 4 Tablet Formulation Tablets/ingredients Per Tablet
  • Mg stearate 1.3 mg Procedure for tablet formulation: ingredients 1 , 2, 3 and 4 are blended in a suitable mixer/biender. Sufficient water is added portion-wise to the blend with careful mixing after each addition until the mass is of a consistency to permit its conversion to wet granules. The wet mass is converted to granules by passing it Rancugh an oscillating granuiator using a No. 8 mesh (2.38 mm) screen. The we? granules are then dried in an oven at 140 * F (60 0 C) until do/. The dry granules are lubricated with ingredient No. 5, and the lubricated granules are compressed on a suitable tablet press, 3ie 5
  • a pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of R(-)-2,4-diamino-5-(2,3-dichlorophenyi)-6-ftuoromethyl pyrimidine in polyethylene glycol with heating. This solution is then diluted with water for injections
  • Ph Eur (to 100 mi).
  • the solution is then rendered sterile by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

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Abstract

La présente invention a pour objet l'utilisation de la R(-)-2,4-diamino-5-(2,3-dichlorophényl)-6-fluorométhylpyrimidine de formule (I) ou des sels, solvates ou promédicaments de qualité pharmaceutique dudit composé, soit en monothérapie, soit en combinaison avec un autre agent thérapeutique, dans le traitement de troubles psychotiques :
PCT/EP2007/051380 2006-02-15 2007-02-13 Utilisation de r-(-)-2,4-diamino-5-(2,3-dichlorophényl)-6-fluorométhylpyrimidine dans le traitement de troubles psychotiques Ceased WO2007093587A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11977085B1 (en) 2023-09-05 2024-05-07 Elan Ehrlich Date rape drug detection device and method of using same

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0196132A2 (fr) * 1985-03-27 1986-10-01 Janssen Pharmaceutica N.V. Dérivés de 1,2-benzisoxazol-3-yle et 1,2-benzisothiazol-3-yle
EP0372934A2 (fr) * 1988-12-07 1990-06-13 The Wellcome Foundation Limited Agents actifs sur le système nerveux central
WO1995032948A1 (fr) * 1994-05-27 1995-12-07 Smithkline Beecham Farmaceutici S.P.A. Derives de quinoline utilises comme antagonistes du recepteur nk3 de la tachykinine
WO1997009317A2 (fr) * 1995-09-05 1997-03-13 Glaxo Group Limited Derive phenylpyrimidine actif optiquement utilise en tant qu'agent analgesique
WO2003099786A2 (fr) * 2002-05-29 2003-12-04 Glaxo Group Limited Composes
WO2005051916A1 (fr) * 2003-11-28 2005-06-09 Glaxo Group Limited 7-[4-(4-chlorobenzyloxy) benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1h-3-benzazepinium maleate ou tosylate en tant qu'agents antipsychotiques

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0196132A2 (fr) * 1985-03-27 1986-10-01 Janssen Pharmaceutica N.V. Dérivés de 1,2-benzisoxazol-3-yle et 1,2-benzisothiazol-3-yle
EP0372934A2 (fr) * 1988-12-07 1990-06-13 The Wellcome Foundation Limited Agents actifs sur le système nerveux central
WO1995032948A1 (fr) * 1994-05-27 1995-12-07 Smithkline Beecham Farmaceutici S.P.A. Derives de quinoline utilises comme antagonistes du recepteur nk3 de la tachykinine
WO1997009317A2 (fr) * 1995-09-05 1997-03-13 Glaxo Group Limited Derive phenylpyrimidine actif optiquement utilise en tant qu'agent analgesique
WO2003099786A2 (fr) * 2002-05-29 2003-12-04 Glaxo Group Limited Composes
WO2005051916A1 (fr) * 2003-11-28 2005-06-09 Glaxo Group Limited 7-[4-(4-chlorobenzyloxy) benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1h-3-benzazepinium maleate ou tosylate en tant qu'agents antipsychotiques

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11977085B1 (en) 2023-09-05 2024-05-07 Elan Ehrlich Date rape drug detection device and method of using same

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